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PLoS Genet. 2014 Aug 7;10(8):e1004517. doi: 10.1371/journal.pgen.1004517. eCollection 2014 Aug.

Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.

Collaborators (317)

Elston RC, Iyengar S, Goddard K, Olson J, Ialacci S, Edwards S, Fondran C, Horvath A, Jun G, Kramp K, Slaughter M, Zaletel E, Sedor JR, Schelling J, Sehgal A, Pickens A, Humbert L, Getz-Fradley L, Adler S, Collins-Schramm HE, Ipp E, Li H, Pahl M, Seldin MF, LaPage J, Walker B, Garcia C, Gonzalez J, Ingram-Drake L, Klag M, Coresh J, Kao L, Mead L, Parekh R, Fink N, Bayton P, Long Y, Wei L, Whitehead T, Knowler WC, Hanson RL, Nelson RG, Jones L, Juan R, Lovelace R, Luethe C, Phillips LM, Sewemaenewa J, Sili I, Waseta B, Saad MF, Guo X, Rotter J, Taylor K, Budgett M, Zager P, Shah V, Scavini M, Bobelu A, Abboud H, Arar N, Duggirala R, Kasinath BS, Plaetke R, Stem M, Goyes C, Sartorio V, Freedman BI, Bowden DW, Satko SC, Rich SS, Warren S, Viverette S, Brooks G, Young R, Winkler C, Smith MW, Thompson M, Hanson R, Briggs JP, Kimmel PL, Rasooly R, Warnock D, Chakraborty R, Dunston GM, Lifton RP, O'Brien SJ, Spielman R, McCarty CA, Starren J, Peissig P, Berg R, Rasmussen L, Linneman J, Miller A, Choudary V, Chen L, Waudby C, Kitchner T, Reeser J, Fost N, Ritchie M, Wilke RA, Chisholm RL, Avila PC, Greenland P, Hayes M, Kho AN, Kibbe WA, Lemke AA, Lowe WL, Smith ME, Wolf WA, Pacheco JA, Thompson WK, Humowiecki J, Law M, Rasmussen-Torvik L, Chute C, Kullo I, Koenig B, de Andrade M, Bielinski S, Pathak J, Savova G, Wu J, Henriksen J, Ding K, Hart L, Palbicki J, Larson EB, Newton K, Ludman E, Spangler L, Hart G, Carrell D, Jarvik G, Crane P, Burke W, Fullerton SM, Brown Trinidad S, Carlson C, McDavid A, Roden DM, Clayton E, Haines JL, Masys DR, Churchill LR, Cornfield D, Crawford D, Darbar D, Denny JC, Malin BA, Ritchie MD, Schildcrout JS, Xu H, Ramirez AH, Basford M, Pulley J, Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, Mcculloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, Mccarroll SA, Langenberg C, Hofmann OM, Dupuis J, Qi L, Segrè AV, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, Bonnycastle LL, Boström KB, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS, Cornelis M, Couper DJ, Crawford G, Doney AS, Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson AU, Johnson PR, Jørgensen T, Kao WH, Klopp N, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken MA, Narisu N, Nilsson P, Owen KR, Payne F, Perry JR, Petersen AK, Platou C, Proença C, Prokopenko I, Rathmann W, Rayner N, Robertson NR, Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P, Sigurdsson G, Sparsø T, Strassburger K, Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam RM, van Haeften TW, van Herpt T, van Vliet-Ostaptchouk JV, Walters G, Weedon MN, Wijmenga C, Witteman J, Bergman RN, Cauchi S, Collins FS, Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter DJ, Hveem K, laakso M, Mohlke KL, Morris AD, Palmer CN, Pramstaller PP, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A, Walker M, Wareham NJ, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Hu FB, Meigs JB, Pankow JS, Pedersen O, Wichmann HE, Barroso I, Florez JC, Frayling TM, Groop L, Sladek R, Thorsteinsdottir U, Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Altshuler D, Boehnke M, Mccarthy MI.

Author information

1
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America; Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
2
Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, Maryland, United States of America.
3
Program on Genomics and Nutrition, School of Public Health, University of California Los Angeles, Los Angeles, California, United States of America; Center for Metabolic Disease Prevention, School of Public Health, University of California Los Angeles, Los Angeles, California, United States of America.
4
Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
5
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America; Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, United States of America.
6
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
7
Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
8
Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.
9
The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
10
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
11
Center for Public Health Genomics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America; Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
12
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
13
Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America.
14
San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, California, United States of America.
15
Department of Epidemiology and Biomedical Informatics, Emory University, Atlanta, Georgia, United States of America.
16
Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
17
Division of Sleep Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
18
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
19
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
20
Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
21
Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
22
Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
23
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America; Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
24
Department of Biology, Center for Health Disparities, East Carolina University, Greenville, North Carolina, United States of America.
25
Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
26
Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
27
Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, United States of America; Jackson State University, Tougaloo College, Jackson, Mississippi, United States of America.
28
Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
29
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
30
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
31
The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
32
The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
33
Laboratory of Personality and Cognition, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
34
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
35
Department of Medicine, Case Western Reserve University, MetroHealth System campus, Cleveland, Ohio, United States of America; Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, United States of America.
36
Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
37
Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America; Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
38
Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America; Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
39
Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
40
Department of Medicine, University of California, San Francisco, California, United States of America.
41
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America.
42
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
43
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; International Epidemiology Institute, Rockville, Maryland, United States of America.
44
Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
45
Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America.
46
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
47
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America.
48
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
49
Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America; Department of Epidemiology, University of Washington, Seattle, Washington, United States of America; Department of Health Services, University of Washington, Seattle, Washington, United States of America.
50
Health Disparities Unit, National Institute on Aging, National Institutes of Health, Baltimore Maryland, United States of America.
51
The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
52
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
53
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
54
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America; Department of Medicine, University of Virginia, Charlottesville, Virginia, United States of America; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, United States of America.
55
Program on Genomics and Nutrition, School of Public Health, University of California Los Angeles, Los Angeles, California, United States of America; Department of Epidemiology, University of California Los Angeles, Los Angeles, California, United States of America; Departments of Epidemiology and Medicine, Brown University, Providence, Rhode Island, United States of America.

Abstract

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.

PMID:
25102180
PMCID:
PMC4125087
DOI:
10.1371/journal.pgen.1004517
[Indexed for MEDLINE]
Free PMC Article

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